The present invention concerns the treatment of steroid induced mood disorders and disorders of the central nervous system (CNS) and in particular new pharmaceuticals for this purpose.
The progesterone metabolites known as pregnanolones have been the subject of various studies, at least partially elucidating their role in the neurological signal system in mammals. The nomenclature differs somewhat in the field, but the pregnanolone group is generally considered to encompass the following compounds: 3alpha-hydroxy-5alpha-pregnan-20-one(allopregnanolone), 3alpha-hydroxy-5beta-pregnan-20-one (pregnanolone), 3beta-hydroxy-5alpha-pregnan-20-one (epiallopregnanolone), and 3beta-hydroxy-5-beta-pregnan-20-one (epipregnanolone).
3alpha-hydroxy-5alpha-pregnan-20-one is an important specific GABA-A {xcex3-aminobutyric acid (A)} receptor enhancer. It has a specific binding site located on the alpha- and/or beta-unit of the GABA-A receptor. It acts by enhancing the effect of GABA on the opening frequency of the GABA-A receptor and the opening duration. It has an effect similar both to benzodiazepines and barbiturates but has a binding site separate from both these compounds. The effect is specific on the GABA-A receptor and can be blocked by the GABA-antagonist picrotoxin. 3alpha-hydroxy-5alpha-prenan-20-one has a CNS-depressing effect and it is possible to induce anaesthesia with a high pharmacological dose. It can also be used as anti-epileptic substance, sleeping-pill and as anti-migraine effect. It has also shown anxiolytic effects in animal experiments. All this in high concentrations and in high doses.
3alpha-hydroxy-5beta-pregnan-20-one, 3alpha-hydroxy-5alpha-pregnan-21-ol-20-one and 3alpha-hydroxy-5beta-pregnan-21-ol-20-one have similar effects as the above-described steroid but are less potent. They have slightly different pharmacogenetic properties suggesting that there might be two binding sites for the steroids on the GABA-A receptor.
3beta-hydroxy-5alpha-pregnan-20-one: This progesterone metabolite is the steroid involved in the present invention, described in more detail below.
3beta-hydroxy-5beta-pregnan-20-one: This steroid seems to have no effect either as a blocker or as an antagonist to the above sedative steroids. The present inventors have also tested 3beta-hydroxy-pregnanolone which is a steroid having a double-bond between the 4th and 5th coal atom and no 5-reduction. This steroid has no effect either as an agonist or blocker or antagonist. Obviously, the pregnanolones in spite of their structural similarities, have highly differing modes of action, if any, in the mammal neurochemical environment.
Steroid induced mood disorders are a frequent problem among women and in particular during the luteal phase of the menstrual cycle. Associated to this, some oral contraceptives have shown to have an negative influence on the CNS, such as mood disorders. Further, many other CNS disorders are believed to be steroid induced. Finally, the development of steroid based anesthetics require the availability of effective anti-anaesthetics.
Prince and Simmons (Neuropharmacology, vol. 32, no. 1, pp. 59-63, 1993) have used a model of membrane fractions of whole male rat brain. In this sub-fraction of whole brain homogenate they have used the binding of a benzodiazepine, 3H-flunitrazepam, as a model for steroid effect and change of GABA-A receptor conformation. This test has been suggested as an indicator of allosteric modulation of the GABA-A receptor. The relationship between the change in flunitrazepam (FNZ) binding and change in chloride flow at GABA-stimulation is uncertain and a change in binding can not be taken as a proof of change in chloride flow through the GABA-receptor or change in GABA-A receptor function. The change in chloride flow is the important effect.
The central question, if there exists a relationship between change in FNZ-binding and neuronal excitability is even less clear and such conclusions can not be drawn from results on FNZ-binding. A change in FNZ-binding properties or absence of such change in binding properties does not imply a change or absence of change in neural activity or GABA-A mediated chloride flow.
It is also well known that the GABA-A receptor contains several sub-units that can be combined in multiple ways. It is known that certain combinations lack steroid recognition site. It is also known that the effect of steroid on the binding of a convulsant substance TBPS differs in different brain regions. Further, it is known that the binding of TBPS varies with the estrus cycle in female rats indicating an effect change related to the ovarian hormone production. These changes related to estrus cycle can not be noticed in male rats used in the studies of Prince and Simmons (supra).
There is no indication in the prior art that 3beta-hydroxy-5alpha-pregnan-20-one by itself causes any measurable CNS-activity changes in vitro or in vivo. On the contrary, the findings are in fact contradictory.
The present invention discloses for the first time a practical use of 3beta-hydroxy-5alpha-pregnan-20-one as a pharmaceutical inter alia for the treatment of steroid induced CNS disorders, mood disorders, memory disorders and for use as an anti-anaestheticum and antisedativum, according to the attached claims.
The invention will be described in closer detail in the following, with reference to the attached drawings, in which
FIG. 1 shows the dosage of 3alpha-hydroxy-5alpha-pregnan-20-one (mg/kg, Y-axis) needed to reach the xe2x80x9csilent secondxe2x80x9d threshold criterion for deep anaesthesia at increasing dosages of 3beta-hydroxy-5beta-pregnan-20-one (mg/kg, X-axis), and
FIG. 2 shows the dosage of 3alpha-hydroxy-5beta-pregnan-20-one (mg/kg, Y-axis) needed to reach the xe2x80x9csilent secondxe2x80x9d threshold criterion for deep anaesthesia at increasing dosages of 3beta-hydroxy-5alpha-pregnan-20-one (mg/kg, X-axis) given simultaneously in an intravenous infusion.
FIG. 3 shows in the effect of local application of the anaesthetic steroid and GABA-A receptor modulator 3alpha-hydroxy-5alpha-pregnan-20-one on the amplitude of the induced population spike (POPSP) in slices from hippocampal CAI region,
FIG. 4 shows the effect of the vehicle and the effect of local application of another anaesthetic steroid, 3alpha-hydroxy-5beta-pregnan-20-one, and
FIG. 5 shows the effect of 3alpha-hydroxy-5alpha-pregnan-20-one together with Muscimol (an agonist to the GABA) on the amplitude of the induced population spike (POPSP) in slices from the hippocampal CAI region.